The Nrf2 transcription factor is master regulator of detoxification and antioxidant mechanisms. Accumulating evidence indicates that Nrf2 dependent gene expression programs preserve organismic integrity and homeostasis. Therefore, Nrf2 function is a topic of high interested for aging research. This proposal is based on two principal hypotheses: 1. Aging associated functional decline is promoted by loss of Nrf2 signal responsiveness. The precise regulation of Nrf2 target genes is failing as organisms age. The contribution of the chromatin organizer and Nrf2 dimerization partner MafS to this age-associated degenerative phenotype will be investigated. 2. Longevity promoting functions of Nrf2 can be regulated by dedicated signaling pathways. The regulation of Nrf2 function is complex and incompletely understood. Especially the molecular mechanisms underlying the regulatory interplay between life extending metabolic signals (caloric restriction / resveratrol) and Nrf2 are not well described. Using newly developed experimental tools for the monitoring of Nrf2 function in vivo and in tissue culture, and automated high throughput RNAi screens a comprehensive study of Nrf2 regulatory mechanism is proposed. The long-term goals of this project are (i) to provide new information on general principles of aging using Nrf2 as a specific, experimentally tractable example, (ii) to develop rational strategies for the delay or reversal of age associated degenerative phenotypes, (iii) to gain a systems level understanding of the interactions between different stress and metabolic signaling pathways that influence lifespan and healthspan. PUBLIC HEALTH RELEVANCE: Oxidative damage to macromolecules, cells and tissues is considered a driver of aging and a major contributor to many diseases that predominantly afflict the elderly. Mechanisms that prevent or delay the progressive accumulation of oxidative damage in the aging organism can promote longevity and allay age-associated diseases. This project will investigate why such defense mechanisms break down as organisms grow old and tries to find ways to prevent or delay that decline.